1. Field of the Invention
The invention relates to the fields of polymer chemistry, pharmacy and medicine and relates to a method for producing a drug delivery system on the basis of polyelectrolyte complexes, which, for example, as a component of implants, releases drugs in the environment of the implant.
2. Discussion of Background Information
For the provision of release or so-called drug delivery systems (DDS) with the release of drugs (AS) at biomedically relevant positions on the one hand a great need exists as well as a great need for action. DDS have been continuously researched from the beginnings around 1940 through the present day. They are an important component in the transfer of new drugs into clinical practice. [B. Malafaya, et al. (2002): Curr. Opinion Solid State Mater. Sci. 6, 283-312 (Part I), 297-312. (Part II)]
New active agent-loaded polymer systems [H. Tamba, et al. (2005). Adv. Drug Deliv. Rev. 57, 357-376; G. B. Sukohorukov, et al. (2005). Small, 182, 194-200.] seem particularly promising for this purpose. In this context on the one hand classic systems of surfactant or (co)polymer liposomes [H. Ringsdorf (1975). Polym. Sci. Polymer Symp. 51, 135-153; D. D. Lasic (1998) Medical applications of Liposomes, Papahadjopoulos D., Ed.; Elsevier; M. Antonietti, S. Förster (2003). Advanced Materials 15, 1323-1333.] can be used. On the other hand, polyelectrolyte hollow capsules [A. I. Petrov, et al. (2005). Biotechnol. Prog. 21, 918-925; K. Köhler, et al. (2004) Macromolecules 37, 9546-9550] render possible the physical inclusion of active ingredients.
Polyelectrolyte complexes (PEC) are generally known. They are produced by complexing oppositely charged polyelectrolytes (PEL). With this complexing, the PEC can be formed in the form of dispersed spherical-like PEC nanoparticles. These PEC nanoparticles are obtained by the controlled mixing of polycation solutions and polyanion solutions in non-stoichiometric molar ratios, [V. A. Kabanov, et al (1984). Pure Appl. Chem, 56, 343-354; B. Philipp, et al. (1989). Prog. Polym. Sci. 14, 91-172]. PEC nanoparticles are composed of a rather hydrophobic charge-compensated core and a hydrophilic shell, which is formed by the respective excess PEL (polycation or polyanion). PEC nanoparticles are interesting among other things for the surface modification of technical substrates, [X. Feng, et al. (2007) Biomacromolecules 8, 2161-2166]. Already preformed nanoparticles can thereby preferentially be bound to the corresponding substrate or the complexing step takes place in the presence of the substrate.
A great potential of the PEC particles is seen for nano carrier systems in the volume phase in the field of biomedicine and pharmacy [P. Dubin, et al. (eds.) (1994) Macromolecular Complexes in Chemistry and Biology, Springer-Verlag].
In this context, studies by Tiyaboonchai [W. Tiyaboonchai et al. (2001) J. Pharm. Sci. 90, 902-914] are known, in which the formulation and characterization of nanoparticles of poly(ethylenimine) (PEI), dextran sulfate (DS) and amphotericin B (AmB) is described. AmB is an antifungal drug for systemic fungal infections, but due to the low water solubility is not absorbed by the gastrointestinal tract. Likewise, the development of a breast cancer therapeutic agent on the basis of chitosan-alginate microparticles has been studied [G. Coppi, et al. (2009), Int. J. Pharmaceut. 367, 127-132], in which the absorption and time-dependent release of Tamoxifen was tested.
Furthermore, the absorption of Salbutamol, a therapeutic agent for asthma, on complex particles from the two oppositely charged proteins gelatin A and gelatin B in the submicrometer range and the delayed release thereof in gastrosimulating liquids is described [A. Tiwari, et al. (2009). Biomacromolecules 10, 184-189]. Salbutamol was added during and after the complexing. As an important propelling power of the release, the osmotic pressure difference between the particle interior and the environment was cited. Also interesting with respect to the invention, are studies on the use of PEC particles as carrier systems in general for proteins [W. Ouyang, et al. (2006). Macromol. Biosci. 6, 929-941], specifically for growth factors (VEGF) (chitosan/dextran sulfate) [M. Huang, et al. (2007) Biomacromolecules 8, 1607-1614], but also for plasmid DNA [W. Tiyaboonchai, et al. (2003) Eur. J. Pharm. Sci. 19, 191-202].
There are disadvantages in the known technical solutions for drug delivery systems above all in the still not yet adequate accuracy with locally controlled releases of drugs at the desired sites as well as in the speed and quantity of the release of the drug.